Journal
JOURNAL OF LIPID RESEARCH
Volume 54, Issue 11, Pages 2979-2987Publisher
ELSEVIER
DOI: 10.1194/jlr.M037754
Keywords
12-HHT; cyclooxygenase; TxAS; mass spectrometry; eicosanoid
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [21390083, 22116001, 22116002, 22790296, 24102522, 25460374]
- Mitsubishi Foundation
- Naito Foundation
- Takeda Science Foundation
- Inamori Foundation
- Japan Society for the Promotion of Science (Global COE program)
- Grants-in-Aid for Scientific Research [21390083, 24102522, 22790296, 22116001, 25460374, 22116002] Funding Source: KAKEN
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12(S)-hydroxyheptadeca-5Z,8 E,10 E-trienoic acid (12-HHT) has long been considered a by-product of thromboxane A(2) (TxA(2)) biosynthesis with no biological activity. Recently, we reported 12-HHT to be an endogenous ligand for BLT2, a low-affinity leukotriene B 4 receptor. To delineate the biosynthetic pathway of 12-HHT, we established a method that enables us to quantify various eicosanoids and 12-HHT using LC-MS/MS analysis. During blood coagulation, 12-HHT levels increased in a time-dependent manner and were relatively higher than those of TxB(2), a stable metabolite of TxA(2). TxB(2) production was almost completely inhibited by treatment with ozagrel, an inhibitor of TxA synthase (TxAS), while 12-HHT production was inhibited by 80-90%. Ozagrel-treated blood also exhibited accumulation of PGD(2) and PGE(2), possibly resulting from the shunting of PGH(2) into synthetic pathways for these prostaglandins. In TxAS-deficient mice, TxB(2) production during blood coagulation was completely lost, but 12-HHT production was reduced by 80-85%. HEK293 cells transiently expressing TxAS together with cyclooxygenase (COX)-1 or COX-2 produced both TxB(2) and 12-HHT from arachidonic acid, while HEK293 cells expressing only COX-1 or COX-2 produced significant amounts of 12-HHT but no TxB(2). These results clearly demonstrate that 12-HHT is produced by both TxAS-dependent and TxAS-independent pathways in vitro and in vivo.
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